Autistic-like Behaviors Research Articles

MTOR inhibitor improves autistic-like behaviors related to Tsc2 haploinsufficiency but not following developmental status epilepticus

BackgroundTuberous sclerosis complex (TSC), a multi-system genetic disorder often associated with autism spectrum disorder (ASD), is caused by mutations of TSC1 or TSC2, which lead to constitutive overactivation of mammalian target of rapamycin (mTOR). In several Tsc1+/- and Tsc2+/- animal models, cognitive and social behavior deficits were reversed by mTOR inhibitors. However, phase II studies have not shown amelioration of ASD and cognitive deficits in individuals with TSC during mTOR inhibitor therapy. We asked here if developmental epilepsy, common in the majority of individuals with TSC but absent in most animal models, could explain the discrepancy.MethodsAt postnatal day P12, developmental status epilepticus (DSE) was induced in male Tsc2+/- (Eker) and wild-type rats, establishing four experimental groups including controls. In adult animals (n = 36), the behavior was assessed in the paradigms of social interaction test, elevated plus-maze, light-dark test, Y-maze, and novel object recognition. The testing was carried out before medication (T1), during a 2-week treatment with the mTOR inhibitor everolimus (T2) and after an 8-week washing-out (T3). Electroencephalographic (EEG) activity was recorded in a separate set of animals (n = 18).ResultsBoth Tsc2+/- mutation and DSE caused social behavior deficits and epileptiform EEG abnormalities (T1). Everolimus led to a persistent improvement of the social deficit induced by Tsc2+/-, while deficits related to DSE did not respond to everolimus (T2, T3).ConclusionsThese findings may contribute to an explanation why ASD symptoms in individuals with TSC, where comorbid early-onset epilepsy is common, were not reliably ameliorated by mTOR inhibitors in clinical studies.

4E-BP2-dependent translation in cerebellar Purkinje cells controls spatial memory but not autism-like behaviors.

Recent studies have demonstrated that selective activation of mammalian target of rapamycin complex 1 (mTORC1) in the cerebellum by deletion of the mTORC1 upstream repressors TSC1 or phosphatase and tensin homolog (PTEN) in Purkinje cells (PCs) causes autism-like features and cognitive deficits. However, the molecular mechanisms by which overactivated mTORC1 in the cerebellum engenders these behaviors remain unknown. The eukaryotic translation initiation factor 4E-binding protein 2 (4E-BP2) is a central translational repressor downstream of mTORC1. Here, we show that mice with selective ablation of 4E-BP2 in PCs display a reduced number of PCs, increased regularity of PC action potential firing, and deficits in motor learning. Surprisingly, although spatial memory is impaired in these mice, they exhibit normal social interaction and show no deficits in repetitive behavior. Our data suggest that, downstream of mTORC1/4E-BP2, there are distinct cerebellar mechanisms independently controlling social behavior and memory formation.

Internet addiction and mental disorders: Clinical effects by self-distancing

We face today the huge and very rapid worldwide growth of behavioural issues related to the use of Internet. The definition of Problematic Internet Use (PIU) refers to new behavioural patterns that can potentially affect in variable degree, from mild to extremely severe, both individual and social wellbeing. PIU is strongly increasing in people affected by different forms of mental disorders and personality disorders, often inducing substantial changes in their clinical phenomenology, with consequent emergence of new symptom and course profiles. On the other side, PIU represents itself with growing frequency as a factor with high potential of inducing progressive psychological and behavioural impairment, with possible negative outcome on personal and psychosocial wellbeing and adjustment, also potentially leading to the development of new specific forms of psychopathology. Among PIU patterns, Internet Addiction (IA) plays a central role, due to its wide diffusion and behavioural as well as interpersonal and social consequences. The worldwide COVID 19 epidemics induced limitations in direct social relationships, such as social distancing, appear to lead to changes of patterns of IA, for an increase of time spent in addictive behaviour and a further reduction of research of interpersonal contacts. Obsessive-compulsive and autistic-like behaviour are differently reinforced by the combined effect of compulsory self distancing and general health concern, but also possibly induced in previously not affected subjects. Anxiety and mood reactivity also contributes to maladjustment profiles. Further evidences and new guide-lines are requested to face this novel and multifactorial social and clinical phenomenon.DisclosureNo significant relationships.

Association Between Gestational Exposure to Toxicants and Autistic Behaviors Using Bayesian Quantile Regression.

Autism spectrum disorder, which is characterized by impaired social communication and stereotypic behaviors, affects 1%-2% of children. Although prenatal exposure to toxicants has been associated with autistic behaviors, most studies have been focused on shifts in mean behavior scores. We used Bayesian quantile regression to assess the associations between log2-transformed toxicant concentrations and autistic behaviors across the distribution of behaviors. We used data from the Maternal-Infant Research on Environmental Chemicals study, a pan-Canadian cohort (2008-2011). We measured metal, pesticide, polychlorinated biphenyl, phthalate, bisphenol-A, and triclosan concentrations in blood or urine samples collected during the first trimester of pregnancy. Using the Social Responsiveness Scale (SRS), in which higher scores denote more autistic-like behaviors, autistic behaviors were assessed in 478 children aged 3-4 years old. Lead, cadmium, and most phthalate metabolites were associated with mild increases in SRS scores at the 90th percentile of the SRS distribution. Manganese and some pesticides were associated with mild decreases in SRS scores at the 90th percentile of the SRS distribution. We identified several monotonic trends in which associations increased in magnitude from the bottom to the top of the SRS distribution. These results suggest that quantile regression can reveal nuanced relationships and, thus, should be more widely used by epidemiologists.

Alterations in Tau Protein Level and Phosphorylation State in the Brain of the Autistic-Like Rats Induced by Prenatal Exposure to Valproic Acid.

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by deficient social interaction and communication besides repetitive, stereotyped behaviours. A characteristic feature of ASD is altered dendritic spine density and morphology associated with synaptic plasticity disturbances. Since microtubules (MTs) regulate dendritic spine morphology and play an important role in spine development and plasticity the aim of the present study was to investigate the alterations in the content of neuronal α/β-tubulin and Tau protein level as well as phosphorylation state in the valproic acid (VPA)-induced rat model of autism. Our results indicated that maternal exposure to VPA induces: (1) decrease the level of α/β-tubulin along with Tau accumulation in the hippocampus and cerebral cortex; (2) excessive Tau phosphorylation and activation of Tau-kinases: CDK5, ERK1/2, and p70S6K in the cerebral cortex; (3) up-regulation of mTOR kinase-dependent signalling in the hippocampus and cerebral cortex of adolescent rat offspring. Moreover, immunohistochemical staining showed histopathological changes in neurons (chromatolysis) in both analysed brain structures of rats prenatally exposed to VPA. The observed changes in Tau protein together with an excessive decrease in α/β-tubulin level may suggest destabilization and thus dysfunction of the MT cytoskeleton network, which in consequence may lead to the disturbance in synaptic plasticity and the development of autistic-like behaviours.

Structural and functional brain-wide alterations in A350V Iqsec2 mutant mice displaying autistic-like behavior

IQSEC2 is an X-linked gene that is associated with autism spectrum disorder (ASD), intellectual disability, and epilepsy. IQSEC2 is a postsynaptic density protein, localized on excitatory synapses as part of the NMDA receptor complex and is suggested to play a role in AMPA receptor trafficking and mediation of long-term depression. Here, we present brain-wide structural volumetric and functional connectivity characterization in a novel mouse model with a missense mutation in the IQ domain of IQSEC2 (A350V). Using high-resolution structural and functional MRI, we show that animals with the A350V mutation display increased whole-brain volume which was further found to be specific to the cerebral cortex and hippocampus. Moreover, using a data-driven approach we identify putative alterations in structure–function relations of the frontal, auditory, and visual networks in A350V mice. Examination of these alterations revealed an increase in functional connectivity between the anterior cingulate cortex and the dorsomedial striatum. We also show that corticostriatal functional connectivity is correlated with individual variability in social behavior only in A350V mice, as assessed using the three-chamber social preference test. Our results at the systems-level bridge the impact of previously reported changes in AMPA receptor trafficking to network-level disruption and impaired social behavior. Further, the A350V mouse model recapitulates similarly reported brain-wide changes in other ASD mouse models, with substantially different cellular-level pathologies that nonetheless result in similar brain-wide alterations, suggesting that novel therapeutic approaches in ASD that result in systems-level rescue will be relevant to IQSEC2 mutations.

Sodium phenylbutyrate reduces repetitive self-grooming behavior and rescues social and cognitive deficits in mouse models of autism.

Autism spectrum disorder (ASD) is a neurodevelopment disorder characterized by deficits in social interaction and restrictive, repetitive, and stereotypical patterns of behavior. However, there is no pharmacological drug that is currently used to target these core ASD symptoms. Sodium phenylbutyrate (NaPB) is a well-known long-term treatment of urea cycle disorders in children. In this study, we assessed the therapeutic effects of NaPB, which is a chemical chaperone as well as histone deacetylase inhibitor on a BTBR T + Itpr3tf/J (BTBR) mice model of ASD. We found that acute and chronic treatment of NaPB remarkably improved, not only core ASD symptoms, including repetitive behaviors and sociability deficit, but also cognitive impairment in the BTBR mice. NaPB substantially induced histone acetylation in the brain of the BTBR mice. Intriguingly, the therapeutic effects of NaPB on autistic-like behaviors, such as repetitive behaviors, impaired sociability, and cognitive deficit also showed in the valproic acid (VPA)-induced mouse model of autism. In addition, pentylenetetrazole (PTZ)-induced seizure was significantly attenuated by NaPB treatment in C57BL/6J and BTBR mice. These findings suggest that NaPB may provide a novel therapeutic approach for the treatment of patients with ASD.

A Novel and Reliable Rat Model of Autism.

Background: Autism spectrum disorders (ASD) is a complex neurodevelopmental disorder that lacks an ideal animal model to recapitulate the disease state of ASD. Previous studies have reported that transplanting gut microbiota of ASD patients into pregnant mice is sufficient to promote the changes of autism-like behavior in offspring. This study aims to explore whether fecal microbiota transplantation (FMT) can be used as a new method to establish the ASD animal model.Methods: We transplanted the fecal sample extract of ASD children into pregnant rats (rFMT) repeatedly to establish an ASD rat model (oFMT) and compare it with the classical valproic acid (VPA) model (oVPA).Results: First, we reveal that oFMT shows hypoevolutism and typical behavioral characteristics of ASD, consistent with the previous study. Second, the gut microbiota of oFMT mainly consists of Firmicutes and Bacteroidetes, recapitulating the abnormal gut microbiota of ASD. In oFMT, the abundance of Lactobacillus and Collinsella increased (Lactobacillus: oFMT 60.16%, oVPA 64.13%, oCON 40.11%; Collinsella: oFMT 3.73%, oVPA 1.39%, oCON 1.28%), compared with oVPA, gut microbiota also showed high consistency. Third, the expression of 5-hydroxytryptamine (5-HT) in oFMT serum increased, γ-aminobutyric acid (GABA) and norepinephrine (NE) in oFMT serum decreased. Fourth, the gut microbiota of oFMT also has some ASD characteristic gut microbiota not found in oVPA. Fifth, pregnant rat with VPA showed significant immune activation, while those with FMT showed relatively minor immune activation.Limitations: Although the mechanism of establishing FMT autism rat model (oFMT) has not clearly defined, the data show that the model has high structural validity, and FMT model is likely to be a new and reliable potential animal model of ASD, and will have potential value in studying gut microbiota of ASD.Conclusions: The FMT autism rat model has high structural validity, and the FMT model is likely to be a new and reliable potential animal model of ASD.

Critical Role of TLR4 on the Microglia Activation Induced by Maternal LPS Exposure Leading to ASD-Like Behavior of Offspring.

Objective: To investigate the role of TLR4 on the microglia activation in the pre-frontal cortex, which leads to autism-like behavior of the offspring induced by maternal lipopolysaccharide (LPS) exposure.Methods: Pregnant TLR4−/− (knockout, KO) and WT (wild type, WT) dams were intraperitoneally injected with LPS or PBS, respectively. The levels of TNFα, IL-1β, and IL-6 in the maternal serum and fetal brain were assessed with ELISA following LPS exposure. The gestation period, litter size and weight of the offspring were evaluated. Three-chamber sociability test, open field test and olfactory habituation/dishabituation test were used to assess the offspring's autism-like behavior at 7 weeks of age. Western blotting was performed to examine the levels of TLR4, Phospho-NFκB p65, IKKα, IBA-1, iNOS, Arg-1, C3, CR3A, NMDAR2A, and Syn-1 expression in the pre-frontal cortex. The morphological changes in the microglia, the distribution and expression of TLR4 were observed by immunofluorescence staining. Golgi-Cox staining was conducted to evaluate the dendritic length and spine density of the neurons in 2-week-old offspring.Results: Maternal LPS stimulation increased serum TNFα and IL-6, as well as fetal brain TNFα in the WT mice. The litter size and the weight of the WT offspring were significantly reduced following maternal LPS treatment. LPS-treated WT offspring had lower social and self-exploration behavior, and greater anxiety and repetitive behaviors. The protein expression levels of TLR4 signaling pathways, including TLR4, Phospho-NFκB p65, IKKα, and IBA-1, iNOS expression were increased in the LPS-treated WT offspring, whereas Arg-1 was decreased. Maternal LPS treatment resulted in the significant reduction in the levels of the synaptic pruning-related proteins, C3 and CR3A. Moreover, the neuronal dendritic length and spine density, as well as the expression levels of the synaptic plasticity-related proteins, NMDAR2A and Syn-1 were reduced in the WT offspring; however, gestational LPS exposure had no effect on the TLR4−/− offspring.Conclusion: Activation of TLR4 signaling pathway following maternal LPS exposure induced the abnormal activation of microglia, which in turn was involved in excessive synaptic pruning to decrease synaptic plasticity in the offspring. This may be one of the reasons for the autism-like behavior in the offspring mice.

A case report of Phelan-McDermid syndrome: preliminary results of the treatment with growth hormone therapy

BackgroundPhelan-McDermid syndrome (PMS), also known as 22q13.3 deletion syndrome, is a rare neurodevelopmental syndrome resulting from a deletion of the distal long arm of chromosome 22.Case presentationWe report a case of a 21 months old Chinese girl presenting with global developmental delay, regression of language skills, unable to understand a few words or walk independently, insomnia, and autism-like behaviors. Copy number variation (CNV) analysis showed a heterozygous loss of SHANK3 gene in the 22q13 region, consistent with a diagnosis of PMS. After treatment with recombinant human growth hormone (rhGH), this patient had an improvement in motor skills and social behaviors. No side effects from rhGH therapy were reported.ConclusionsThis is the first report of using rhGH to treat a Chinese girl diagnosed with PMS. We speculate rhGH could be a reasonable alternative choice for PMS treatment with similar clinical outcomes in comparison to insulin-like growth factor-1(IGF-1). However, further clinical trials are needed to confirm this hypothesis.

Autistic-like behavior, spontaneous seizures, and increased neuronal excitability in a Scn8a mouse model.

Patients with SCN8A epileptic encephalopathy exhibit a range of clinical features, including multiple seizure types, movement disorders, and behavioral abnormalities, such as developmental delay, mild-to-severe intellectual disability, and autism. Recently, the de novo heterozygous SCN8A R1620L mutation was identified in an individual with autism, intellectual disability, and behavioral seizures without accompanying electrographic seizure activity. To date, the effects of SCN8A mutations that are primarily associated with behavioral abnormalities have not been studied in a mouse model. To better understand the phenotypic and functional consequences of the R1620L mutation, we used CRISPR/Cas9 technology to generate mice expressing the corresponding SCN8A amino acid substitution. Homozygous mutants exhibit tremors and a maximum lifespan of 22 days, while heterozygous mutants (RL/+) exhibit autistic-like behaviors, such as hyperactivity and learning and social deficits, increased seizure susceptibility, and spontaneous seizures. Current clamp analyses revealed a reduced threshold for firing action potentials in heterozygous CA3 pyramidal neurons and reduced firing frequency, suggesting that the R1620L mutation has both gain- and loss-of-function effects. In vivo calcium imaging using miniscopes in freely moving RL/+ mutants showed hyperexcitability of cortical excitatory neurons that is likely to increase seizure susceptibility. Finally, we found that oxcarbazepine and Huperzine A, a sodium channel blocker and reversible acetylcholinesterase inhibitor, respectively, were capable of conferring robust protection against induced seizures in RL/+ mutants. This mouse line will provide the opportunity to better understand the range of clinical phenotypes associated with SCN8A mutations and to develop new therapeutic approaches.

Folic acid ameliorates neonatal isolation-induced autistic like behaviors in rats: epigenetic modifications of BDNF and GFAP promotors.

The current study investigated the role of epigenetic dysregulation of brain derived neurotrophic factor (BDNF) and glial fibrillary acidic protein (GFAP) genes and oxidative stress as possible mechanisms of autistic-like behaviors in neonatal isolation model in rats and the impact of folic acid administration on these parameters. Forty Wistar albino pups were used as follows: control, folic acid administered, isolated, and isolated folic acid treated groups. Isolated pups were separated from their mothers for 90 min daily from postnatal day (PND) 1 to 11. Pups (isolated or control) received either the vehicle or folic acid (4 mg/kg/day) orally from PND 1 to 29. Behavioral tests were done from PND 30 to 35. Oxidative stress markers and antioxidant defense in the frontal cortex homogenate were determined. DNA methylation of BDNF and GFAP genes was determined by qPCR. Histopathological examination was carried out. Neonatal isolation produced autistic-like behaviors that were associated with BDNF and GFAP hypomethylation, increased oxidative stress, increased inflammatory cell infiltration, and structural changes in the frontal cortex. Folic acid administration concurrently with isolation reduced neonatal isolation-induced autistic-like behaviors, decreased oxidative stress, regained BDNF and GFAP gene methylation, and ameliorated structural changes in the frontal cortices of isolated folic acid treated rats. Novelty: Neonatal isolation induces "autistic-like" behavior and these behaviors are reversed by folic acid supplementation. Neonatal isolation induces DNA hypomethylation of BDNF and GFAP, increased oxidative stress markers, and neuroinflammation. All of these changes were reversed by daily folic acid supplementation.

The Multi-Targeting Ligand ST-2223 with Histamine H3 Receptor and Dopamine D2/D3 Receptor Antagonist Properties Mitigates Autism-Like Repetitive Behaviors and Brain Oxidative Stress in Mice.

Autism spectrum disorder (ASD) is a complex heterogeneous neurodevelopmental disorder characterized by social and communicative impairments, as well as repetitive and restricted behaviors (RRBs). With the limited effectiveness of current pharmacotherapies in treating repetitive behaviors, the present study determined the effects of acute systemic treatment of the novel multi-targeting ligand ST-2223, with incorporated histamine H3 receptor (H3R) and dopamine D2/D3 receptor affinity properties, on ASD-related RRBs in a male Black and Tan BRachyury (BTBR) mouse model of ASD. ST-2223 (2.5, 5, and 10 mg/kg, i.p.) significantly mitigated the increase in marble burying and self-grooming, and improved reduced spontaneous alternation in BTBR mice (all p < 0.05). Similarly, reference drugs memantine (MEM, 5 mg/kg, i.p.) and aripiprazole (ARP, 1 mg/kg, i.p.), reversed abnormally high levels of several RRBs in BTBR (p < 0.05). Moreover, ST-2223 palliated the disturbed anxiety levels observed in an open field test (all p < 0.05), but did not restore the hyperactivity parameters, whereas MEM failed to restore mouse anxiety and hyperactivity. In addition, ST-2223 (5 mg/kg, i.p.) mitigated oxidative stress status by decreasing the elevated levels of malondialdehyde (MDA), and increasing the levels of decreased glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT) in different brain parts of treated BTBR mice (all p < 0.05). These preliminary in vivo findings demonstrate the ameliorative effects of ST-2223 on RRBs in a mouse model of ASD, suggesting its pharmacological prospective to rescue core ASD-related behaviors. Further confirmatory investigations on its effects on various brain neurotransmitters, e.g., dopamine and histamine, in different brain regions are still warranted to corroborate and expand these initial data.

Associations between Prenatal Education, Breastfeeding and Autistic-Like Behaviors in Pre-Schoolers.

This study aimed to investigate the association between prenatal education and autistic-like behaviors of preschoolers as well as the mediating role of breastfeeding in their associations. A cross-sectional study via a structured questionnaire was conducted with 67,578 preschool children and parents from Longhua District of Shenzhen, China. Hierarchical logistic regression models were performed to explore the associations between maternal participation in prenatal education and autistic-like behaviors in preschoolers, as well as the mediating effect of breastfeeding in the associations. After controlling for potential confounders, logistic regression analysis indicated that maternal participation in prenatal education could significantly increase the prevalence of breastfeeding, and the strength of the association was enhanced with the increase frequency of prenatal education visits (ORs ranging from 1.191 to 1.899). While both maternal participation in prenatal education (ORs ranging from 0.732 to 0.798) and breastfeeding (OR = 0.773) were significantly associated with the lower presence of autistic-like behaviors in preschoolers. The crossover analysis indicated that children with both maternal prenatal education and breastfeeding had the lower risk of presence of autistics-like behaviors (OR = 0.569). Furthermore, mediation analysis illustrated that breastfeeding mediated the association between maternal participation in prenatal education and the presence of autistic-like behaviors in preschoolers, with a mediating effect of approximately 14.3%. Our findings suggest that maternal participation in prenatal education is significantly associated with a decreased risk of autistic-like behaviors in preschool children through increased breastfeeding in the mothers who attended prenatal education.

Maternal Diabetes-Induced Suppression of Oxytocin Receptor Contributes to Social Deficits in Offspring.

Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders characterized by impaired skills in social interaction and communication in addition to restricted and repetitive behaviors. Many different factors may contribute to ASD development; in particular, oxytocin receptor (OXTR) deficiency has been reported to be associated with ASD, although the detailed mechanism has remained largely unknown. Epidemiological study has shown that maternal diabetes is associated with ASD development. In this study, we aim to investigate the potential role of OXTR on maternal diabetes-mediated social deficits in offspring. Our in vitro study of human neuron progenitor cells showed that hyperglycemia induces OXTR suppression and that this suppression remains during subsequent normoglycemia. Further investigation showed that OXTR suppression is due to hyperglycemia-induced persistent oxidative stress and epigenetic methylation in addition to the subsequent dissociation of estrogen receptor β (ERβ) from the OXTR promoter. Furthermore, our in vivo mouse study showed that maternal diabetes induces OXTR suppression; prenatal OXTR deficiency mimics and potentiates maternal diabetes-mediated anxiety-like behaviors, while there is less of an effect on autism-like behaviors. Additionally, postnatal infusion of OXTR partly, while infusion of ERβ completely, reverses maternal diabetes-induced social deficits. We conclude that OXTR may be an important factor for ASD development and that maternal diabetes-induced suppression of oxytocin receptor contributes to social deficits in offspring.

Perinatal exposure to BDE-47 exacerbated autistic-like behaviors and impairments of dendritic development in a valproic acid-induced rat model of autism

Perinatal exposure to polybrominated diphenyl ethers (PBDEs) may be a potential risk factor for autism spectrum disorders (ASD). BDE-47 is one of the most common PBDEs and poses serious health hazards on the central nervous system (CNS). However, effects of perinatal exposure to BDE-47 on social behaviors and the potential mechanisms are largely unexplored. Thus, we aimed to investigate whether BDE-47 exposure during gestation and lactation led to autistic-like behaviors in offspring rats in the present study. Valproic acid (VPA), which is widely used to establish animal model of ASD, was also adopted to induce autistic-like behaviors. A battery of tests was conducted to evaluate social and repetitive behaviors in offspring rats. We found that perinatal exposure to BDE-47 caused mild autistic-like behaviors in offspring, which were similar but less severe to those observed in pups maternally exposed to VPA. Moreover, perinatal exposure to BDE-47 aggravated the autistic-like behaviors in pups maternally exposed to VPA. Abnormal dendritic development is known to be deeply associated with autistic-like behaviors. Golgi-Cox staining was used to observe the morphological characteristics of dendrites in the prefrontal cortex of pups. We found perinatal exposure to BDE-47 reduced dendritic length and complexity of branching pattern, and spine density in the offspring prefrontal cortex, which may contribute to autistic-like behaviors observed in the present study. Perinatal exposure to BDE-47 also exacerbated the impairments of dendritic development in pups maternally exposed to VPA. Besides, our study also provided the evidence that the inhibition of BDNF-CREB signaling, a key regulator of dendritic development, may be involved in the dendritic impairments induced by perinatal exposure to BDE-47 and/or VPA, and the consequent autistic-like behaviors.

Combined the GABA-A and GABA-B receptor agonists attenuates autistic behaviors in a prenatal valproic acid-induced mouse model of autism

Autism spectrum disorder (ASD) is an immensely challenging developmental disorder characterized primarily by two core behavioral symptoms of social communication deficits and restricted/repetitive behaviors. Investigating the etiological process and identifying an appropriate therapeutic target remain as formidable challenges to overcome ASD due to numerous risk factors and complex symptoms associated with the disorder. Among the various mechanisms that contribute to ASD, the maintenance of excitation and inhibition balance emerged as a key factor to regulate proper functioning of neuronal circuitry. In this study, we employed prenatally exposed to valproic acid (VPA) to establish a validated ASD mouse model and found impaired inhibitory gamma-aminobutyric acid (GABAergic) neurotransmission through a presynaptic mechanism in these model mice, which was accompanied with decreased GABA release and GABA-A and GABA-B receptor subunits expression. And acute administration of individual GABA-A or GABA-B receptor agonists partially reversed autistic-like behaviors in the model mice. Furthermore, acute administration of the combined GABA-A and GABA-B receptor agonists palliated sociability deficits, anxiety and repetitive behaviors in the animal model of autistic-like behaviors, demonstrating the therapeutic potential of above cocktail in the treatment of ASD.

Dual Profile of Environmental Enrichment and Autistic-Like Behaviors in the Maternal Separated Model in Rats.

Background: Environmental Enrichment (EE) has been suggested as a possible therapeutic intervention for neurodevelopmental disorders such as autism. Although the benefits of this therapeutic method have been reported in some animal models and human studies, the unknown pathophysiology of autism as well as number of conflicting results, urge for further examination of the therapeutic potential of EE in autism. Therefore, the aim of this study was to examine the effects of environmental enrichment on autism-related behaviors which were induced in the maternal separation (MS) animal model. Material and Methods: Maternally separated (post-natal day (PND) 1–14, 3 h/day) and control male rats were at weaning (PND21) age equally divided into rats housed in enriched environment and normal environment. At adolescence (PND42–50), the four groups were behaviorally tested for direct social interaction, sociability, repetitive behaviors, anxiety behavior, and locomotion. Following completion of the behavioral tests, the blood and brain tissue samples were harvested in order to assess plasma level of brain derived neurotrophic factor (BDNF) and structural plasticity of brain using ELISA and stereological methods respectively. Results: We found that environmental enrichment reduced repetitive behaviors but failed to improve the impaired sociability and anxiety behaviors which were induced by maternal separation. Indeed, EE exacerbated anxiety and social behaviors deficits in association with increased plasma BDNF level, larger volume of the hippocampus and infra-limbic region and higher number of neurons in the infra-limbic area (p < 0.05). Conclusion: We conclude that environmental enrichment has a significant improvement effect on the repetitive behavior as one of the core autistic-like behaviors induced by maternal separation but has negative effect on the anxiety and social behaviors which might have been modulated by BDNF.

Exposure to the plasticizer, Di-(2-ethylhexyl) phthalate during juvenile period exacerbates autism-like behavior in adult BTBR T + tf/J mice due to DNA hypomethylation and enhanced inflammation in brain and systemic immune cells

Epigenetic modifications are known to play a crucial role in the behavioral modifications through regulation of gene expression. Environmental factors are known to regulate genetic transcription through DNA methylation which is one of the mechanisms of epigenetic modification. Di-2-ethylhexyl phthalate (DEHP) is one of the most abundant phthalate plasticizers in day-to-day products. Prenatal/postnatal DEHP administration has been reported to cause inflammation as well as behavioral dysregulation, however it is not known if exposure to DEHP during juvenile stage affects peripheral/neuronal inflammation and autism-like symptoms in BTBR mice at adulthood. This study investigated effect of DEHP exposure during juvenile period on DNA methylation (global DNA methylation/DNMT1 expression) and inflammation (IL-17A, IL-6, MCP-1, TNF-α) in CD4 + T cells/CD11c + DCs and cortex, and autism-like symptoms (three-chambered sociability test, self-grooming and marble burying test) in asocial BTBR and social C57 mice at adulthood. Our data reveal that BTBR mice exposed to DEHP during juvenile period have hypomethylated DNA/DNMT1 expression in CD11c + DCs and cortex as compared to vehicle-exposed BTBR mice. It was associated with upregulated inflammation in periphery [plasma IL-6/IL-17A, CD11c + DCs (IL-6/MCP-1/TNF-α), and CD4+ T cells (IL-17A)] and cortex (IL-6, MCP-1, TNF-α), and aggravation in autism-like symptoms in DEHP-treated BTBR mice. These data propose that exposure of DEHP during juvenile period may affect autism-like behavior and inflammation in BTBR mice at adulthood through epigenetic regulation. Therefore, underlying genetic predisposition may play a crucial role in worsening of autistic symptoms in ASD subjects in adulthood if they are exposed to environmental pollutants such as DEHP during juvenile period.

The Effect of Environmental Enrichment with Autistic-like Behavior Symptoms on a Rattus norvegicus Model

AIM: The aim of this study was to investigate the effect of environmental enrichment with autistic-like behavior symptoms on a Rattus norvegicus model.&#x0D; METHODS: The post-test control only group design is used in this study. The study sample is baby of Rattus norvegicus Sprague Dawley strain who were born to cows who gave birth for the 1st time and children from cows who had been injected with valproic acid (VPA) who gave birth for the 1st time. This study has been divided into three groups, namely, negative control, positive control, and intervention: the negative control group; the VPA without enrichment as positive control; and the VPA group with enrichment as intervention group. One-way ANOVA tests were used to data analysis. Data are processed using SPSS version 23.0.&#x0D; RESULTS: This study showed that the mean of social interaction in the negative control group was 359.11 ± 39.33 s higher than the positive control, namely, 182.00 ± 35.80 s and 244.56 ± 19.06 s for intervention. The mean of repetitive movement in the negative control group was 48.00 ± 9.03 s lower than the positive control, namely, 212.11 ± 41.43 s and intervention 160.00 ± 18.91 s. There has been an influence of environmental enrichment with social interaction and repetitive movements on a Rattus norvegicus model (p &lt; 0.05).&#x0D; CONCLUSION: This study confirmed that there has been an influence of environmental enrichment with social interaction and repetitive movements on a Rattus norvegicus model.